Is it safe to take amitriptyline and Wellbutrin (bupropion) together?

Combining Amitriptyline and Wellbutrin (Bupropion)

Yes, amitriptyline and bupropion can be taken together, but this combination requires careful monitoring due to a significant drug interaction: bupropion inhibits CYP2D6, which metabolizes amitriptyline, potentially increasing amitriptyline levels and toxicity risk. 1

Key Drug Interaction

Bupropion and its metabolites are CYP2D6 inhibitors, which means coadministration with drugs metabolized by CYP2D6—including tricyclic antidepressants like amitriptyline—can increase exposure to these substrates. 1 This is particularly important because tricyclic antidepressants have a narrow therapeutic index, meaning small increases in blood levels can lead to serious adverse effects.

Dosing Adjustments Required

• When combining these medications, you will likely need to decrease the amitriptyline dose to account for increased drug exposure from CYP2D6 inhibition 1
• Start with low initial doses of bupropion and increase gradually, as recommended for all combinations involving bupropion 1
• The typical bupropion dosing ranges from 100-450 mg daily, while amitriptyline typically ranges from 75-225 mg daily when used alone 2, 3

Seizure Risk Considerations

Use extreme caution because both medications can lower the seizure threshold, and combining them increases this risk. 1

• Bupropion carries a 0.1% seizure risk when used for smoking cessation 4
• The combination of drugs that lower seizure threshold requires starting with low initial bupropion doses and gradual titration 1
• Absolutely avoid this combination in patients with brain metastases, history of seizures, or elevated seizure risk 4

Clinical Evidence for Combination Therapy

While there are no controlled studies specifically examining bupropion combined with tricyclic antidepressants 4, there is evidence supporting combination strategies:

• A clinical case series found that combining bupropion with other antidepressants in partial responders showed greater symptomatic improvement in 70% of patients (19/27 subjects) 5
• The combination appeared safe with conservative dosing and close monitoring, though adverse effects included sexual dysfunction (41%), insomnia (22%), anergy (15%), and tremor (11%) 5
• No seizures occurred in this series, though sample size was limited 5

Historical Context on Tricyclic-Stimulant Combinations

An older guideline noted that combining tricyclic antidepressants (specifically desipramine) with methylphenidate showed "no clinical evidence of unique or serious side effects beyond those attributable to [the tricyclic] alone" 4. However, the use of tricyclics in general has fallen off due to association with sudden death in five children a decade prior to that publication 4, highlighting the inherent risks of this drug class.

Monitoring Requirements

When combining these medications, monitor for:

• Anticholinergic toxicity (dry mouth, urinary retention, constipation, confusion) from elevated amitriptyline levels 1, 2, 3
• Cardiovascular effects, particularly QT prolongation and arrhythmias associated with amitriptyline 4
• Neuropsychiatric symptoms including agitation, restlessness, and mood changes 4
• Seizure activity, especially during dose escalation 1

Common Pitfalls to Avoid

• Do not use standard amitriptyline doses when combining with bupropion—dose reduction is necessary 1
• Do not combine with MAO inhibitors—at least 14 days must elapse between MAOI discontinuation and bupropion initiation 1
• Minimize or avoid alcohol consumption during treatment, as rare neuropsychiatric events and reduced alcohol tolerance have been reported with bupropion 1
• Be aware of false-positive amphetamine screens in patients taking bupropion; confirmatory testing with gas chromatography/mass spectrometry is needed 1

Bottom Line

This combination can be used effectively for treatment-resistant depression, but requires dose adjustment of amitriptyline downward, careful titration of bupropion, and vigilant monitoring for seizures and anticholinergic toxicity. The pharmacokinetic interaction is predictable and manageable with appropriate precautions.